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A novel myelin protein zero (V136G) homozygous mutation causing late onset demyelinating polyneuropathy with brain white matter lesions
Clinical Neurology and Neurosurgery 113 (2011) 243–244
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
A novel myelin protein zero (V136G) homozygous mutation causing late onset demyelinating polyneuropathy with brain white matter lesions K. Reyes-Marin a,∗ , J. Jimenez-Pancho b , Lidia Pozo c , M. Garcia-Villanueva d , G. de Blas a , J.M. Vazquez c , A. Jimenez-Escrig c a
Department of Clinical Neurophysiology, Hospital Ramon y Cajal, Ctra. de Colmenar Viejo km. 9, 100 28034 Madrid, Spain Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla, Spain Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain d Department of Pathology, Hospital Ramon y Cajal, Madrid, Spain b c
a r t i c l e
i n f o
Article history: Received 6 April 2010 Accepted 25 October 2010 Available online 1 February 2011 Keywords: Charcot-Marie-Tooth Demyelinating Myelin protein zero Polyneuropathy White matter lesions
a b s t r a c t Although less common than peripheral myelin protein 22 (PMP22) duplication, there are mutations in myelin protein zero (MPZ) responsible for Charcot-Marie-Tooth disease (CMT) with a number of different clinical profiles. We report here a novel MPZ homozygous mutation, with a peculiar pattern characterized by a late-onset demyelinating profile. In addition, the patient presented brain white matter lesions seemingly ascribable to the mutation. © 2010 Elsevier B.V. All rights reserved.
1. Introduction
2. Clinical report
Mutations in MPZ are responsible for about 5% of the autosomal dominant demyelinating forms (CMT1B), but there are a number of reports of mutations in this gene with a DI-CMT (intermediate demyelinating and axonal), axonal (CMT2I; CMT2J), severe infantile (CMT3), and autosomal recessive demyelinating polyneuropathy (CMT4E), and even a case with liability to pressure palsy (HNPP) has been described [1,6,9,10]. Usual clinical presentation of MPZ mutations is demyelinating polyneuropathy with early onset, before adolescence, but some MPZ mutations can cause axonal polyneuropathy with later age of onset, around the 30s, which causes milder functional impairment [11]. We report here a novel missense MPZ homozygous mutation with a peculiar clinical pattern characterized by a late-onset demyelinating profile. In addition, the patient presented brain white matter lesions seemingly ascribable to the MPZ mutation.
A 65-year-old woman, daughter of non-consanguineous parents with an asymptomatic sister, began at age 45 with troubles when walking fast. Her symptoms slowly progressed and at age 61 she developed ataxia and intention tremor. Examination showed lower limb paresis, tendon hyporreflexia, impaired vibration and arthrokinetic sensitivities and unbalanced gait. Remaining examination was unremarkable except for overweight. Blood test for systemic diseases was normal or negative. Neurophysiological study showed denervation potentials in cuadriceps and deltoid and decreased motor and sensory velocities, severely in lower limbs – peroneal velocities of 20 m/s –, and moderately in the median nerves (34 m/s). Motor and sensory evoked potential amplitudes were decreased in the lower but not in the upper limbs. A sural biopsy at age 47, showed lost of myelinic fibers without myelin ovoids. At that time the CSF disclosed normal cell count, glucose and proteins and an IgG of 4.2 mg/dL. With the clinical suspicion of a chronic demyelinating polyneuropathy she underwent several courses of oral prednisone, high-dose immunoglobulins and plasmapheresis without benefit. At age 62, a brain magnetic resonance image presented multiple confluent lesions in brain white matter (Fig. 1a) involving corpus callosum and U-association fibers. A year later, a new sural biopsy was done that do not display inflammatory signs but severe loss of myelinic fiber occurs (Fig. 1b).
∗ Corresponding author. Tel.: +34 1 3368398; fax: +34 1 3369016. E-mail addresses: [email protected], eli za [email protected] (K. Reyes-Marin). 0303-8467/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2010.10.015
244
K. Reyes-Marin et al. / Clinical Neurology and Neurosurgery 113 (2011) 243–244
Most mutations are located on its extracellular domain [4,7]. The p.V136G mutation is located in the extracellular domain of MPZ and involves an amino acid that seems to have a role in adhesivity of tetramers to form compact myelin. A mutation p.V136E has been previously reported causing a very severe phenotype, which can be explained by a more intense effect of this change on protein function [1]. This new mutation has a very interesting clinical profile, with a sporadic presentation due to the recessive pattern of transmission, and a clinical onset in adult age, which is more common in dominant transmission pattern. Besides, lateonset cases are axonal polyneuropathies, whilst in this case it was demyelinating. In addition, the patient had asymptomatic white matter lesions on brain MRI, with characteristics of demyelination such as corpus callosum and U-association fibers involvement [2]. CNS white matter involvement has been reported in other CMT cases, usually CBJ1 mutations [3]. A case with an MPZ gene H39P mutation has been recently reported associating multiple sclerosis although paradoxically MPZ is not expressed in CNS [5]. Nevertheless, CNS involvement has not been ruled out systematically with MRI in CMT patients so there can be a reporting bias. References
Fig. 1. (a) MRI FLAIR T2-sequence shows hyperintense posterior periventricle, subcortical and in semioval centers white matter lesions. (b) Semi-thin, Toluidine Blue ×40, showing a reduction in the number of myelinic fibers, mainly the larger ones, and Schwann cell proliferation with onion bulbs and some scarce myelin ovoids and regenerative clusters.
A genetic screening for polyneuropathies was undergone ruling out PMP22 duplication or deletion, and point mutations in PMP22, GJB1, and EGR2. In the sequencing of MPZ, a novel c.T407C missense mutation homozygous was found in exon 3 that generated a p.V136G change. In addition, an heterozygous c.A274G point mutation was found in exon 3 of LITAF/SIMPLE gene sequence, that generated a p.I92V change, which has been previously reported as an asymptomatic polymorphism [8]. Other relatives were unavailable for testing this mutation. 3. Discussion MPZ functions as an adhesion molecule in compact myelin and has an extracellular, transmembrane and cytoplasmic domain.
[1] Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, et al. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype–phenotype correlation. Ann Neurol 2002;51:190– 201. [2] Charil A, Yousry TA, Rovaris M, Barkhof F, De SN, Fazekas F, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of “no better explanation”. Lancet Neurol 2006;5:841–52. [3] Hanemann CO, Bergmann C, Senderek J, Zerres K, Sperfeld AD. Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation. Arch Neurol 2003;60:605–9. [4] Hayasaka K, Himoro M, Wang Y, Takata M, Minoshima S, Shimizu N, et al. Structure and chromosomal localization of the gene encoding the human myelin protein zero (MPZ). Genomics 1993;17:755–8. [5] Kilfoyle DH, Dyck PJ, Wu Y, Litchy WJ, Klein DM, Dyck PJ, et al. Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis. J Neurol Neurosurg Psychiatry 2006;77:963–6. [6] Magot A, Latour P, Mussini JM, Mourtada R, Guiheneuc P, Pereon Y. A new MPZ mutation associated with a mild CMT1 phenotype presenting with recurrent nerve compression. Muscle Nerve 2008;38:1055–9. [7] Matsuyama W, Nakagawa M, Takashima H, Osame M. Altered trafficking and adhesion function of MPZ mutations and phenotypes of Charcot-Marie-Tooth disease 1B. Acta Neuropathol 2002;103::501–8. [8] Saifi GM, Szigeti K, Wiszniewski W, Shy ME, Krajewski K, HausmanowaPetrusewicz I, et al. SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum Mutat 2005;25:372–83. [9] Shy ME. Peripheral neuropathies caused by mutations in the myelin protein zero. J Neurol Sci 2006;242:55–66. [10] Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, et al. Phenotypic clustering in MPZ mutations. Brain 2004;127:371–84. [11] Auer-Grumbach M, Strasser-Fuchs S, Robl T, Windpassinger C, Wagner K. Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene. Neurology 2003;61:1435–7.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
A novel myelin protein zero (V136G) homozygous mutation causing late onset demyelinating polyneuropathy with brain white matter lesions K. Reyes-Marin a,∗ , J. Jimenez-Pancho b , Lidia Pozo c , M. Garcia-Villanueva d , G. de Blas a , J.M. Vazquez c , A. Jimenez-Escrig c a
Department of Clinical Neurophysiology, Hospital Ramon y Cajal, Ctra. de Colmenar Viejo km. 9, 100 28034 Madrid, Spain Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla, Spain Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain d Department of Pathology, Hospital Ramon y Cajal, Madrid, Spain b c
a r t i c l e
i n f o
Article history: Received 6 April 2010 Accepted 25 October 2010 Available online 1 February 2011 Keywords: Charcot-Marie-Tooth Demyelinating Myelin protein zero Polyneuropathy White matter lesions
a b s t r a c t Although less common than peripheral myelin protein 22 (PMP22) duplication, there are mutations in myelin protein zero (MPZ) responsible for Charcot-Marie-Tooth disease (CMT) with a number of different clinical profiles. We report here a novel MPZ homozygous mutation, with a peculiar pattern characterized by a late-onset demyelinating profile. In addition, the patient presented brain white matter lesions seemingly ascribable to the mutation. © 2010 Elsevier B.V. All rights reserved.
1. Introduction
2. Clinical report
Mutations in MPZ are responsible for about 5% of the autosomal dominant demyelinating forms (CMT1B), but there are a number of reports of mutations in this gene with a DI-CMT (intermediate demyelinating and axonal), axonal (CMT2I; CMT2J), severe infantile (CMT3), and autosomal recessive demyelinating polyneuropathy (CMT4E), and even a case with liability to pressure palsy (HNPP) has been described [1,6,9,10]. Usual clinical presentation of MPZ mutations is demyelinating polyneuropathy with early onset, before adolescence, but some MPZ mutations can cause axonal polyneuropathy with later age of onset, around the 30s, which causes milder functional impairment [11]. We report here a novel missense MPZ homozygous mutation with a peculiar clinical pattern characterized by a late-onset demyelinating profile. In addition, the patient presented brain white matter lesions seemingly ascribable to the MPZ mutation.
A 65-year-old woman, daughter of non-consanguineous parents with an asymptomatic sister, began at age 45 with troubles when walking fast. Her symptoms slowly progressed and at age 61 she developed ataxia and intention tremor. Examination showed lower limb paresis, tendon hyporreflexia, impaired vibration and arthrokinetic sensitivities and unbalanced gait. Remaining examination was unremarkable except for overweight. Blood test for systemic diseases was normal or negative. Neurophysiological study showed denervation potentials in cuadriceps and deltoid and decreased motor and sensory velocities, severely in lower limbs – peroneal velocities of 20 m/s –, and moderately in the median nerves (34 m/s). Motor and sensory evoked potential amplitudes were decreased in the lower but not in the upper limbs. A sural biopsy at age 47, showed lost of myelinic fibers without myelin ovoids. At that time the CSF disclosed normal cell count, glucose and proteins and an IgG of 4.2 mg/dL. With the clinical suspicion of a chronic demyelinating polyneuropathy she underwent several courses of oral prednisone, high-dose immunoglobulins and plasmapheresis without benefit. At age 62, a brain magnetic resonance image presented multiple confluent lesions in brain white matter (Fig. 1a) involving corpus callosum and U-association fibers. A year later, a new sural biopsy was done that do not display inflammatory signs but severe loss of myelinic fiber occurs (Fig. 1b).
∗ Corresponding author. Tel.: +34 1 3368398; fax: +34 1 3369016. E-mail addresses: [email protected], eli za [email protected] (K. Reyes-Marin). 0303-8467/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2010.10.015
244
K. Reyes-Marin et al. / Clinical Neurology and Neurosurgery 113 (2011) 243–244
Most mutations are located on its extracellular domain [4,7]. The p.V136G mutation is located in the extracellular domain of MPZ and involves an amino acid that seems to have a role in adhesivity of tetramers to form compact myelin. A mutation p.V136E has been previously reported causing a very severe phenotype, which can be explained by a more intense effect of this change on protein function [1]. This new mutation has a very interesting clinical profile, with a sporadic presentation due to the recessive pattern of transmission, and a clinical onset in adult age, which is more common in dominant transmission pattern. Besides, lateonset cases are axonal polyneuropathies, whilst in this case it was demyelinating. In addition, the patient had asymptomatic white matter lesions on brain MRI, with characteristics of demyelination such as corpus callosum and U-association fibers involvement [2]. CNS white matter involvement has been reported in other CMT cases, usually CBJ1 mutations [3]. A case with an MPZ gene H39P mutation has been recently reported associating multiple sclerosis although paradoxically MPZ is not expressed in CNS [5]. Nevertheless, CNS involvement has not been ruled out systematically with MRI in CMT patients so there can be a reporting bias. References
Fig. 1. (a) MRI FLAIR T2-sequence shows hyperintense posterior periventricle, subcortical and in semioval centers white matter lesions. (b) Semi-thin, Toluidine Blue ×40, showing a reduction in the number of myelinic fibers, mainly the larger ones, and Schwann cell proliferation with onion bulbs and some scarce myelin ovoids and regenerative clusters.
A genetic screening for polyneuropathies was undergone ruling out PMP22 duplication or deletion, and point mutations in PMP22, GJB1, and EGR2. In the sequencing of MPZ, a novel c.T407C missense mutation homozygous was found in exon 3 that generated a p.V136G change. In addition, an heterozygous c.A274G point mutation was found in exon 3 of LITAF/SIMPLE gene sequence, that generated a p.I92V change, which has been previously reported as an asymptomatic polymorphism [8]. Other relatives were unavailable for testing this mutation. 3. Discussion MPZ functions as an adhesion molecule in compact myelin and has an extracellular, transmembrane and cytoplasmic domain.
[1] Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, et al. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype–phenotype correlation. Ann Neurol 2002;51:190– 201. [2] Charil A, Yousry TA, Rovaris M, Barkhof F, De SN, Fazekas F, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of “no better explanation”. Lancet Neurol 2006;5:841–52. [3] Hanemann CO, Bergmann C, Senderek J, Zerres K, Sperfeld AD. Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation. Arch Neurol 2003;60:605–9. [4] Hayasaka K, Himoro M, Wang Y, Takata M, Minoshima S, Shimizu N, et al. Structure and chromosomal localization of the gene encoding the human myelin protein zero (MPZ). Genomics 1993;17:755–8. [5] Kilfoyle DH, Dyck PJ, Wu Y, Litchy WJ, Klein DM, Dyck PJ, et al. Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis. J Neurol Neurosurg Psychiatry 2006;77:963–6. [6] Magot A, Latour P, Mussini JM, Mourtada R, Guiheneuc P, Pereon Y. A new MPZ mutation associated with a mild CMT1 phenotype presenting with recurrent nerve compression. Muscle Nerve 2008;38:1055–9. [7] Matsuyama W, Nakagawa M, Takashima H, Osame M. Altered trafficking and adhesion function of MPZ mutations and phenotypes of Charcot-Marie-Tooth disease 1B. Acta Neuropathol 2002;103::501–8. [8] Saifi GM, Szigeti K, Wiszniewski W, Shy ME, Krajewski K, HausmanowaPetrusewicz I, et al. SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum Mutat 2005;25:372–83. [9] Shy ME. Peripheral neuropathies caused by mutations in the myelin protein zero. J Neurol Sci 2006;242:55–66. [10] Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, et al. Phenotypic clustering in MPZ mutations. Brain 2004;127:371–84. [11] Auer-Grumbach M, Strasser-Fuchs S, Robl T, Windpassinger C, Wagner K. Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene. Neurology 2003;61:1435–7.